1. Field of the Invention
The present invention relates generally to the synthesis of compounds comprising heterocyclic rings. In one specific embodiment, the invention provides novel tetracyclic benzimidazole derivative compounds as well as novel combinatorial libraries comprised of such compounds.
2. Background Information
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested, one or more structures is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional xe2x80x9cone-at-a-timexe2x80x9d synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional xe2x80x9cone-at-a-timexe2x80x9d synthesis methods, except over a time frame of years or even decades. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as tetracyclic benzimidazole derivative compounds.
Combinatorial approaches have recently been extended to xe2x80x9corganic,xe2x80x9d or non-peptide, libraries. For example, Zambias et al. (U.S. Pat. No. 5,712,171) describe a method of generating libraries that contain aminimides, oxazolones, sulfonylaminides and phosphonylaminides as the core structure in spatially arranged arrays. Combinatorial chemical methods have been applied to a limited number of heterocyclic compounds, as described, for example, in Wilson et al., Molecular Diversity, 3:95-112 (1998); U.S. Pat. Nos. 5,288,514; 5,324,483; and Goff et al., J. Org. Chem., 60:5748-5749 (1995). See also U.S. Pat. Nos. 5,549,974 and 5,506,337. Combinatorial chemical methods have even been extended to benzimidazole compounds, as described, for example, in Tumelty et al., Tetr. Ltrs., 40:6185-6188 (1999); Yeh et al., Synlett, 6:810-812 (1999); Sun et al., Bioorg. and Med. Chem. Ltrs., 8:361-364 (1998); Huang et al., Tetr. Ltrs., 40:2665-2668 (1999); Phillips and Wei, Tetr. Ltrs., 37:4887-4890 (1996); and Mayer et al., Tetr. Ltrs., 39:6655-6658 (1998). However, the heterocyclic libraries to date contain compounds of limited diversity and complexity.
Substituent limitations have been overcome for mixtures of peptides and peptidomimetics through the use of solid phase techniques versus solution-phase. An important step in the development of solid-phase techniques was the discovery of methods to prepare large numbers of individual compounds simultaneously, as described, for example, by Houghten in U.S. Pat. No. 4,631,211. These solid phase methods, however, have rarely been applied to the syntheses of complex heterocyclic structures. Therefore a need exists to develop more complex xe2x80x9corganicxe2x80x9d libraries based on heterocyclic medicinal compounds which would need less time and effort in the synthesis and testing required to bring an organic pharmaceutical product to fruition. In short, improved methods for generating therapeutically useful heterocyclic compounds, such as tetracyclic benzimidazole derivatives, are desired.
Tetracyclic benzimidazole derivative compounds have been the subject of investigation in a number of different biological areas. For example, tetracyclic benzimidazole derivatives have been proposed as useful as antidepressants (DE 2051962 (1971)). Tetracyclic benzimidazole derivatives have also been the subject of serial chemical synthesis. See, for example, DE 2051962 (1971); Herkaoui et al., Synth. Commun., 25:3287-92 (1995); Herkaoui et al., Synth. Commun., 25:1027-33 (1995); and Duncan et al., J. Heterocycl. Chem., 10:65-70 (1973). However, more complex benzimidazole derivatives, especially those that are tetracyclic and, more especially, those that have a substituent other than hydrogen have been difficult to attain.
This invention satisfies this need and provides related advantages as well. The present invention overcomes the known limitations to classical serial organic synthesis of tetracyclic benzimidazole derivatives, for example, as well as the shortcomings of combinatorial chemistry related to tetracyclic benzimidazole derivatives. The present invention allows for rapid generation of large diverse libraries of complex tetracyclic benzimidazole derivatives as discrete molecules. The present invention can utilize a readily available pool of building blocks that can be incorporated into the various regions of the molecule. Furthermore, the method of making the present invention allows for the use of building blocks that contain a wide range of diverse functionality. Such building blocks can provide combinatorial libraries that consist of large numbers as well as combinatorial libraries that are extremely diverse with respect to the functionality contained within those libraries. The present invention combines the techniques of solid-phase synthesis of tetracyclic benzimidazole derivatives and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new tetracyclic benzimidazole derivative compounds.
The present invention relates to novel tetracyclic benzimidazole derivative compounds of the following formula: 
wherein R1 to R10 have the meanings provided below.
The invention further relates to combinatorial libraries containing two or more such compounds, and to methods of generating tetracyclic benzimidazole derivative compounds.